Optimizing B-lymphocyte Therapeutic Targeting Strategies in Autoimmune Diabetes

描述(由申请人提供)：本申请寻求资助我对自身免疫性1型糖尿病(T1D)的发病机制和可能的临床可翻译干预措施进行的科学研究。这些研究将作为我未来研究计划的基础，为我担任学术教职奠定基础。拥有临床DVM的初步背景为我提供了广泛的基础，在此基础上，我使用人类自身免疫性疾病的小鼠模型建立了我的科学研究生涯。我在2011年冬天顺利完成了我的博士学位，并继续朝着成为一名独立研究员的目标努力。在我的博士工作中研究了B淋巴细胞介导的T细胞依赖性疾病系统性红斑狼疮(SLE)后，我希望通过过渡到研究T细胞介导的B淋巴细胞依赖性疾病T1D来扩大我的自身免疫知识基础。在大约一年前完成了这一转变后，我的近期目标是继续建立在我对自身免疫性疾病发病机制的知识基础上，并为这一领域的研究获得新的工具。资助这项提案将使我能够扩大我对自身免疫的知识，并熟悉其他研究技术。此外，这项工作以及R01在未来几年应用的想法的进展应该会有几个出版物。这项提议带来的所有这些努力将极大地增加我作为一名独立学术教员在下一份工作中取得成功的机会。杰克逊实验室是利用人类疾病的小鼠模型进行这项研究的理想地点。该研究所拥有最先进的科学设施以及丰富的知识渊博的教职员工来协助我的工作。此外，杰克逊实验室为来自世界各地的重要外部研究人员提供了演讲的场所，包括每周一次的系列讲座和年度会议。美国国立卫生研究院还批准了一项研究伦理方面的持续培训计划。我的导师David Serreze博士是自身免疫性糖尿病领域的世界知名高级研究员，已从许多成功的实习生毕业，担任学术界和工业界的独立职位。他的实验室和资源都建立得很好，资金也很充足，他致力于支持我的努力。我的合作导师Kevin Mills博士也是他所在领域的领导者，他最近发表了关于免疫学领域的重要著作，这些领域是这项提案的关键要素，并承诺以任何可能的方式帮助我实现这项申请的目标。杰克逊实验室及其工作人员将确保我得到一切必要的支持，以成功完成这项提案的科学目标，并在我向独立研究人员过渡的过程中得到帮助。在人类和NOD小鼠模型中，T1D最终都是由T细胞介导的自身免疫破坏胰岛素产生的胰腺？细胞。然而，在NOD小鼠中，也可能在人类中，B淋巴细胞在驱动致糖尿病的T细胞反应中发挥着关键作用。这项应用的科学目标是寻求优化针对T1D的B淋巴细胞靶向治疗干预。在NOD小鼠疾病发展的早期阶段，几种不同的B淋巴细胞定向治疗已经成功地减缓了向T1D的进展，包括利妥沙米布样抗CD20抗体和BAFF阻断。然而，目前只有在表现出持续高水平的T1D的迹象后，才能确定T1D的未来高风险人群。细胞破坏，如循环中的自身抗体的存在。因此，临床上可翻译的T1D干预必须在开始时有效 疾病发展的后期阶段。在新近发病的人类T1D患者中，使用CD20特异性利妥昔单抗的瞬时治疗在临床疾病缓解方面只提供了轻微的有效。这一微弱效应的一个可能解释可能源于我们团队之前的发现，即NOD小鼠中的一些B淋巴细胞群体，包括那些浸润性胰岛的B淋巴细胞群体，对利妥昔单抗类抗CD20治疗的缺失具有抵抗力。这项提案的一个目标是 了解抵抗抗CD20介导的缺失的B淋巴细胞亚群在T1D进展的不同阶段在多大程度上起作用，并探索抑制这些细胞的替代治疗方法。另一个目标是确定B淋巴细胞对抗原的亲和力成熟在T1D发病机制中的重要性，并包括测试从淋巴瘤领域借用的针对这一过程的新治疗方法。当在T1D发育的后期阶段启动时，联合疗法可能获得最佳治疗结果，本提案中的实验将解决这一可能性。这项建议的总体重要性在于确定B淋巴细胞导向的T1D疗法在疾病发展的后期阶段最有效，因为这些信息在临床上具有最高的可翻译相关性。

DESCRIPTION (provided by applicant): This application seeks funding for my scientific investigations into the pathogenesis of and possible clinically translatable interventions for autoimmune type 1 diabetes (T1D). These studies will serve as a basis for my future research program, positioning me for an academic faculty position. Having an initial background as a clinical DVM provides me a broad base on which I am building my scientific research career using mouse models of human autoimmune diseases. I successfully completed my Ph.D. in the winter of 2011 and am continuing to work towards my goal of becoming an independent researcher. Having studied the B-lymphocyte mediated, T-cell dependent disease systemic lupus erythematosus (SLE) for my Ph.D. work, I wished to broaden my autoimmunity knowledge base by transitioning to investigating the T-cell mediated, B lymphocyte dependent disease, T1D. Having made this transition approximately a year ago, my immediate goals are to continue building upon my knowledge of autoimmune disease pathogenesis as well as gain new tools for this area of research. Funding of this proposal would allow me to expand my knowledge of autoimmunity as well as familiarize myself with additional research techniques. In addition, several publications should be possible from this work as well as the progression of ideas for an R01 application in the coming years. All of these efforts enabled with this proposal will greatly increase my chances of success in my next position as an independent academic faculty member. The Jackson Laboratory is an ideal location to perform the studies in this proposal using mouse models of human disease. The institute has state of the art scientific facilities as well as a wealth of exceptionally knowledgeable faculty and staff to assist me with my work. In addition, The Jackson Laboratory provides venues in which important outside researchers from around the world come to speak including a weekly lecture series as well as annual conferences. An NIH-approved program is also in place for continued training in research ethics. My mentor, Dr. David Serreze, is a world-renowned senior researcher in the field of autoimmune diabetes and has graduated many successful trainees to independent positions in both academia and industry. His laboratory and resources are well established and well funded and he is committed to supporting my endeavors. My co-mentor Dr. Kevin Mills is also a leader in his field, having recently published important works on immunological areas key to elements of this proposal and has pledged to assist me in any way possible in pursuing the aims in this application. The Jackson Laboratory and its personnel will ensure I receive all the support necessary to successfully complete the scientific goals of this proposal as well as aid in my transition to an independent researcher. T1D in both humans and the NOD mouse model ultimately results from T cell mediated autoimmune destruction of insulin producing pancreatic ? cells. However, in NOD mice, and also likely in humans, B- lymphocytes play a key role in driving diabetogenic T-cell responses. The scientific goals of this application seek to optimize B-lymphocyte targeted therapeutic interventions for T1D. Several different B-lymphocyte directed therapies have been successful at attenuating progression to T1D when initiated at early stages of disease development in NOD mice including the rituxamib-like anti-CD20 antibody and BAFF blockade. However, humans at high future risk for T1D can currently only be identified after manifesting signs of ongoing high levels of ? cell destruction such as the presence of circulating autoantibodies. Thus, clinically translatable T1D interventions must be effective when initiated at late stages of disease development. In recent onset human T1D patients, transient therapy with the CD20 specific rituximab antibody provided only marginally effective at clinical disease attenuation. A possible explanation for this weak effect may stem from previous findings by our group that some B-lymphocyte populations in NOD mice, including those infiltrating pancreatic islets, are resistant to deletion by rituximab-like anti-CD20 therapy. One goal in this proposal is to understand to what extent B-lymphocyte subpopulations that are resistant to anti-CD20 mediated deletion contribute to various stages of T1D progression, and to investigate alternative therapeutic approaches to repress these cells. Another goal is to determine the importance of B-lymphocyte affinity maturation for antigen in T1D pathogenesis and includes the testing of a novel therapeutic approach borrowed from the lymphoma field that targets this process. When initiated at late stages of T1D development, the best therapeutic outcomes may be obtained with combination therapies, and the experiments in this proposal will address this possibility. The overall importance of this proposal lies in the identification of B-lymphocyte directed T1D therapies most effective at late stages of disease development as this information will be of highest clinically translatable relevance.